TY - JOUR
T1 - Dickkopf-like 1 regulates postpubertal spermatocyte apoptosis and testosterone production
AU - Dakhova, Olga
AU - O'Day, Diana
AU - Kinet, Noe
AU - Yucer, Nur
AU - Wiese, Mary
AU - Shetty, Gunapala
AU - Ducy, Patricia
N1 - Copyright:
Copyright 2011 Elsevier B.V., All rights reserved.
PY - 2009/1
Y1 - 2009/1
N2 - Dickkopf-like 1 (Dkkl 1) encodes a glycoprotein secreted by postmeiotic male germ cells. We report here that adult Dkkl1-deficient males have elevated sperm counts caused by a decrease in postpubertal spermatocyte apoptosis and display, upon aging, increased local production of testosterone. Molecular analyses identified the Fas death ligand (FasL) as a target for Dkkl 1 pro-apoptotic activity in adult mice. Accordingly, adult FasL-deficient gld mice display an increased sperm count and decreased spermatocyte apoptosis phenotype similar to the one observed in Dkkl1-deficient mice. We also show thatthe elevated testosterone level observed in aging Dkkl1-deficient males is secondary to increased expression in Leydig cells of CYP11A and CYP17, two genes implicated in steroidogenesis. Furthermore, treatment of Leydig cells with Dkkl1 decreases DNA binding and transcriptional activity of steroidogenic factor 1, a pivotal regulator of gene expression in testis. Thus, this study establishes Dkkl1 as a negative regulator of adulttestis homeostasis and identifies a novel, Dkkl1/FasL-dependent, regulation that specifically controls the number of postpubertal spermatocytes.
AB - Dickkopf-like 1 (Dkkl 1) encodes a glycoprotein secreted by postmeiotic male germ cells. We report here that adult Dkkl1-deficient males have elevated sperm counts caused by a decrease in postpubertal spermatocyte apoptosis and display, upon aging, increased local production of testosterone. Molecular analyses identified the Fas death ligand (FasL) as a target for Dkkl 1 pro-apoptotic activity in adult mice. Accordingly, adult FasL-deficient gld mice display an increased sperm count and decreased spermatocyte apoptosis phenotype similar to the one observed in Dkkl1-deficient mice. We also show thatthe elevated testosterone level observed in aging Dkkl1-deficient males is secondary to increased expression in Leydig cells of CYP11A and CYP17, two genes implicated in steroidogenesis. Furthermore, treatment of Leydig cells with Dkkl1 decreases DNA binding and transcriptional activity of steroidogenic factor 1, a pivotal regulator of gene expression in testis. Thus, this study establishes Dkkl1 as a negative regulator of adulttestis homeostasis and identifies a novel, Dkkl1/FasL-dependent, regulation that specifically controls the number of postpubertal spermatocytes.
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U2 - 10.1210/en.2008-0673
DO - 10.1210/en.2008-0673
M3 - Article
C2 - 18818293
AN - SCOPUS:58149478500
SN - 0013-7227
VL - 150
SP - 404
JO - Endocrinology
JF - Endocrinology
IS - 1
ER -